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In silico analysis of the cyclophilin repertoire of apicomplexan parasites.

Krücken J, Greif G, von Samson-Himmelstjerna G - Parasit Vectors (2009)

Bottom Line: In addition, cyclosporine is known to exhibit anti-parasitic effects on a wide range of organisms including several apicomplexa.In order to obtain new non-immunosuppressive drugs targeting apicomplexan cyclophilins, a profound knowledge of the cyclophilin repertoire of this phylum would be necessary.The genomes of apicomplexa harbor a cyclophilin repertoire that is at least as complex as that of most fungi.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Parasitology, University of Veterinary Medicine Foundation, Bünteweg 17, 30559 Hannover, Germany. juergen.kruecken@tiho-hannover.de.

ABSTRACT

Background: Cyclophilins (Cyps) are peptidyl cis/trans isomerases implicated in diverse processes such as protein folding, signal transduction, and RNA processing. They are also candidate drug targets, in particular for the immunosuppressant cyclosporine A. In addition, cyclosporine is known to exhibit anti-parasitic effects on a wide range of organisms including several apicomplexa. In order to obtain new non-immunosuppressive drugs targeting apicomplexan cyclophilins, a profound knowledge of the cyclophilin repertoire of this phylum would be necessary.

Results: BLAST and maximum likelihood analyses identified 16 different cyclophilin subfamilies within the genomes of Cryptosporidium hominis, Toxoplasma gondii, Plasmodium falciparum, Theileria annulata, Theileria parva, and Babesia bovis. In addition to good statistical support from the phylogenetic analysis, these subfamilies are also confirmed by comparison of cyclophilin domain architecture. Within an individual genome, the number of different Cyp genes that could be deduced varies between 7-9 for Cryptosporidia and 14 for T. gondii. Many of the putative apicomplexan cyclophilins are predicted to be nuclear proteins, most of them presumably involved in RNA processing.

Conclusion: The genomes of apicomplexa harbor a cyclophilin repertoire that is at least as complex as that of most fungi. The identification of Cyp subfamilies that are specific for lower eukaryotes, apicomplexa, or even the genus Plasmodium is of particular interest since these subfamilies are not present in host cells and might therefore represent attractive drug targets.

No MeSH data available.


Domain architecture and genomic organization of PPIA-like Cyps. (A) PPIA-like cytosolic Cyps. For each Cyp, proteins domains are shown in the upper and exon/intron structure in the lower panel. Proteins and genes are presented by lines, domains and exons are highlighted by boxes. Separate scale bars are given for protein and genome scemes. (B) Cyps with apicoplast localization signal. Species are abbreviated as in Fig. 1. Cyp_ABH, ABH-type Cyp domain (CD accession-no.: [cd01926]); SP, signal peptide; AP, apicolast transit signal.
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Figure 2: Domain architecture and genomic organization of PPIA-like Cyps. (A) PPIA-like cytosolic Cyps. For each Cyp, proteins domains are shown in the upper and exon/intron structure in the lower panel. Proteins and genes are presented by lines, domains and exons are highlighted by boxes. Separate scale bars are given for protein and genome scemes. (B) Cyps with apicoplast localization signal. Species are abbreviated as in Fig. 1. Cyp_ABH, ABH-type Cyp domain (CD accession-no.: [cd01926]); SP, signal peptide; AP, apicolast transit signal.

Mentions: The prototypical Cyps in humans and S. pombe, HsPPIA and SpCyp1, respectively, are closely related as shown in Figure 1. They form a cluster together with additional human paralogs such as PPIE, PPIF and PPIAL4A-G. The corresponding putative Cyps in apicomplexa, ChCyp17.9, BbCyp23.7, PfCyp19, ChCyp18.4, TgCyp18.8, and TgCyp18.9 (Figure 2A), form a related but separate cluster, i.e. SpCyp1 is significantly more closely related to HsPPIA, HsPPIE, and HsPPIF than to any of the apicomplexan Cyps. C. hominis and T. gondii encode two distinct putative members of this PPIA-like subfamily in their genomes. Due to their very high expression levels and their cytoplasmic localization, cytoplasmic Cyps containing a Cyp_ABH type domain (CD database accession-no [cd01926]) are considered to be the most important receptors for CsA leading to inactivation of the cytosolic calcineurins [39]. Indeed, mutations in PfCyp19 appear to be sufficient to confer resistance to CsA to P. falciparum [25].


In silico analysis of the cyclophilin repertoire of apicomplexan parasites.

Krücken J, Greif G, von Samson-Himmelstjerna G - Parasit Vectors (2009)

Domain architecture and genomic organization of PPIA-like Cyps. (A) PPIA-like cytosolic Cyps. For each Cyp, proteins domains are shown in the upper and exon/intron structure in the lower panel. Proteins and genes are presented by lines, domains and exons are highlighted by boxes. Separate scale bars are given for protein and genome scemes. (B) Cyps with apicoplast localization signal. Species are abbreviated as in Fig. 1. Cyp_ABH, ABH-type Cyp domain (CD accession-no.: [cd01926]); SP, signal peptide; AP, apicolast transit signal.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713222&req=5

Figure 2: Domain architecture and genomic organization of PPIA-like Cyps. (A) PPIA-like cytosolic Cyps. For each Cyp, proteins domains are shown in the upper and exon/intron structure in the lower panel. Proteins and genes are presented by lines, domains and exons are highlighted by boxes. Separate scale bars are given for protein and genome scemes. (B) Cyps with apicoplast localization signal. Species are abbreviated as in Fig. 1. Cyp_ABH, ABH-type Cyp domain (CD accession-no.: [cd01926]); SP, signal peptide; AP, apicolast transit signal.
Mentions: The prototypical Cyps in humans and S. pombe, HsPPIA and SpCyp1, respectively, are closely related as shown in Figure 1. They form a cluster together with additional human paralogs such as PPIE, PPIF and PPIAL4A-G. The corresponding putative Cyps in apicomplexa, ChCyp17.9, BbCyp23.7, PfCyp19, ChCyp18.4, TgCyp18.8, and TgCyp18.9 (Figure 2A), form a related but separate cluster, i.e. SpCyp1 is significantly more closely related to HsPPIA, HsPPIE, and HsPPIF than to any of the apicomplexan Cyps. C. hominis and T. gondii encode two distinct putative members of this PPIA-like subfamily in their genomes. Due to their very high expression levels and their cytoplasmic localization, cytoplasmic Cyps containing a Cyp_ABH type domain (CD database accession-no [cd01926]) are considered to be the most important receptors for CsA leading to inactivation of the cytosolic calcineurins [39]. Indeed, mutations in PfCyp19 appear to be sufficient to confer resistance to CsA to P. falciparum [25].

Bottom Line: In addition, cyclosporine is known to exhibit anti-parasitic effects on a wide range of organisms including several apicomplexa.In order to obtain new non-immunosuppressive drugs targeting apicomplexan cyclophilins, a profound knowledge of the cyclophilin repertoire of this phylum would be necessary.The genomes of apicomplexa harbor a cyclophilin repertoire that is at least as complex as that of most fungi.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute for Parasitology, University of Veterinary Medicine Foundation, Bünteweg 17, 30559 Hannover, Germany. juergen.kruecken@tiho-hannover.de.

ABSTRACT

Background: Cyclophilins (Cyps) are peptidyl cis/trans isomerases implicated in diverse processes such as protein folding, signal transduction, and RNA processing. They are also candidate drug targets, in particular for the immunosuppressant cyclosporine A. In addition, cyclosporine is known to exhibit anti-parasitic effects on a wide range of organisms including several apicomplexa. In order to obtain new non-immunosuppressive drugs targeting apicomplexan cyclophilins, a profound knowledge of the cyclophilin repertoire of this phylum would be necessary.

Results: BLAST and maximum likelihood analyses identified 16 different cyclophilin subfamilies within the genomes of Cryptosporidium hominis, Toxoplasma gondii, Plasmodium falciparum, Theileria annulata, Theileria parva, and Babesia bovis. In addition to good statistical support from the phylogenetic analysis, these subfamilies are also confirmed by comparison of cyclophilin domain architecture. Within an individual genome, the number of different Cyp genes that could be deduced varies between 7-9 for Cryptosporidia and 14 for T. gondii. Many of the putative apicomplexan cyclophilins are predicted to be nuclear proteins, most of them presumably involved in RNA processing.

Conclusion: The genomes of apicomplexa harbor a cyclophilin repertoire that is at least as complex as that of most fungi. The identification of Cyp subfamilies that are specific for lower eukaryotes, apicomplexa, or even the genus Plasmodium is of particular interest since these subfamilies are not present in host cells and might therefore represent attractive drug targets.

No MeSH data available.